The skin of a living thing becomes aged as it grows older. In order to delay this skin aging, extensive efforts have been made, and the questions of what is the essence of skin aging and why does the skin become aged have been successively brought up. Generally, skin aging is classified into two classes depending on its cause.
The first is intrinsic aging, that is, the structure and the physiological function of the skin deteriorate as it ages. The second is extrinsic aging, which is caused by accumulated stresses such as UV radiation. Particularly, UV radiation is a well-known cause of aging. In case when skin is radiated under UV for a long time, the stratum corneum of skin becomes thicker and collagen is denatured and thereby skin loses its elasticity. Thus, skin aging is accompanied by several functional, and structural changes.
As the structural changes caused by skin aging, the epidermis, dermis and hypoderm of the skin become thinner. In addition, dermal ECM (extracellular matrix), which takes charge of skin elasticity and elongation, is deteriorated because the components of the ECM denatured. ECM is mainly composed of two components, i.e. about 2˜4% of elastic fiber and about 70˜80% of collagen. In the process of skin aging, the collagen production reduces rapidly, and this reduction is caused by several factors in biosynthesis. For example, a matrix metallo protease such as collagenase is activated to decompose collagen, resulting in the reduction of collagen in the skin. The reduction of collagen in the dermis of skin causes the skin to become rough and wrinkled, that is, the skin becomes aged.
In order to suppress the collagen-reduction, which is a cause of wrinkling, some materials have been developed for use. Specially, retinoids such as retinol and retinoic acid have been known to be very effective in lessening skin wrinkles. (Dermatology therapy, 1998, 16, 357˜364)
In spite of anti-wrinkle efficacy, retinoids have some drawbacks in that they cause irritation to the skin with a small quantity and they are easily oxidized in the air due to their instability, so that they are limitated in utilization. In order to stabilize retinoids, many studies have been made, however, the irritation of retinoid to the skin has not yet been fully solved. That is, problems in the safety on the skin remain unsolved.
Retinoids include retinol, retinoic acid and their derivatives. They exhibit various biological activities, and as an example involved in the skin, the effects on abnormal keratinization or on pimple were reported. Also, concerning their involvement in skin wrinkles, it is that they can promote the biosynthesis of collagen and inhibit the activity of collagenase, i.e. an enzyme for decomposing collagen (The Journal of Investigative Dermatology, 1991, 96, 975˜978).
Up to now, retinoids have been developed as follows: In the first stage, simple derivatives of retinol or retinoic acid were developed, and as such derivative, there is a retinyl palmitate. In the next stage, a retinoid derivative prepared by using benzoic acid named arotinoid was developed (J. Med. Chem, 1988, 31, 2182˜2192). Recently, a compound called heteroarotinoid has been developed, in which a heteroatom is introduced into the benzene ring of the arotinoid (J. Med. Chem., 1999, 42, 4434˜4445). The present invention provides a retinoid derivative including hydroxy pyranone, instead of benzoic acid having a heteroatom.
Retinoids are reported to exhibit a biological effect on the skin by acting with an intercellular receptor called a retinoic receptor (British Journal of dermatology, 1999, 140, 12˜17). The structural features of retinoids are resulted from tetramethyl cyclohexane, unsaturated carbon bonds and carboxylic acid. In particular, carboxylic acid moiety is an essential part, which can be easily transformed into anion when the retinoids are acting with the receptor (Chem. Pharm. Bull, 2001, 49, 501˜503).
Based on the above results, researches have been made to lessen toxicity, irritation and instability of the retinoid derivatives while maintaining their intrinsic effects.
Under this circumstance, the present inventors have studied to find a novel type of retinoid that having reduced skin irritation and increased stability in the external formulation for skin care, and invented a desired type of retinoid.
In addition, 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one and its derivatives are known as skin-whitening agents. (U.S. Pat. No. 5,523,421; Bioorganic & Medicinal chemistry letter, 1996, 6, 1303˜1308). In addition to its whitening efficacy, 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one is reported to be very effective in inhibiting skin wrinkle (European Journal of Pharmacology, 2001, 411, 169˜174).
Considering of structural feature, 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one has a 4-positioned carbonyl group and a 5-positioned enolic hydroxy group. The enolic hydroxy group can be easily transformed into anion, to be used in the form of carboxylic acid. In the present invention, this structural feature of 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one was used in synthesizing novel retinoid. The present inventors found that a novel retinoid, i.e. a novel 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one derivative synthesized in the present invention, have excellent safety to the skin and improved stability in the formulations. That is, the retinoid of the present invention does not cause skin irritation, discoloration and odorizing. Based on this finding, the present invention has been completed.
Therefore, an object of the invention is to provide a novel hydroxy pyranone derivative as a novel type of retinoid, which can prevent skin wrinkle and has excellent safety to the skin and improved stability in the formulations.
Another object of the present invention is to provide a method for preparing the hydroxy pyranone derivative.
A further object of the present invention is to show compatibility of the hydroxy pyranone derivative to medicines or external applications for skin care.